Identification of new compounds for use in pharmaceutical preparations is an important part of the search for more reliable and effective therapies. However just as important is the development and modification of known compounds, reducing the risks associated with a new drug candidate and significantly reducing the development and cost to bring the drug to clinical development.
Many drugs fail in clinical trials either because their physical properties (particularly solubility) make them difficult to formulate, or because of a poor therapeutic index that leads to toxic effects during the high drug concentrations that occur just after dosing. Other short comings include poor absorption, poor bioavailability, instability, systemic side effects due to an inability to target the drugs, and the inability to control their biodistribution, metabolism and renal or hepatic clearance once administered. Similarly some current products on the market can be improved with regards to such issues.
A number of approaches have been tried to improve a pharmaceutical compound's profile including the formulation of the pharmaceutical agent in a liposome, micellar or polymeric micelle formulation, as well as covalent attachment of the pharmaceutical agent to a hydrophilic polymer backbone.
The characteristics of an ideal profile modifying agent include being a well defined structure, allowing precise control of the absorption, distribution, metabolism and excretion (ADME) characteristics (also referred to as pharmacokinetics) of the compound in question and advantageously being able to carry multiple compounds per agent or construct. The toxicity of a compound in question can be ameliorated through its controlled release from the said agent or construct, the body only being exposed to therapeutic plasma concentrations of the compound.
In recent years, dendritic macromolecules have been found to have increasing applications in biotechnology and pharmaceutical applications. Dendritic macromolecules are a special class of polymers with densely branched structures that are characterized by higher concentrations of functional groups per unit of molecular volume than ordinary polymers. There are four subclasses of macromolecules: random hyperbranched polymers; dendrigraft polymers; dendritic motifs; and dendrimers, classified on the basis of the relative degree of structural control present in each of the dendritic architectures. The unique properties of dendrimers in particular, such as their high degree of branching, multivalency, globular architecture and well-defined molecular weight, make them promising new scaffolds for drug delivery. In the past decade, research has increased on the design and synthesis of biocompatible dendrimers and their application to many areas of bioscience including drug delivery.
The potential utility of dendritic polymers both as drug delivery vectors and pharmaceutical actives has received increasing interest in recent years1,18. However, whilst the literature is replete with reports of, for example, synthetic schemes for dendrimer assembly, descriptions of dendrimer-drug interactions and drug loading efficiencies and, increasingly, in vitro evaluations of dendrimer interactions with cell lines2,3, there is very little information describing the fundamental pharmacokinetic and metabolic fate of dendrimers.
The interaction of dendrimers with intestinal tissues has also been the subject of several studies4-11 and whilst trends in permeability and cytotoxicity with surface charge and surface functionality have been established, relatively few studies have described the fate of dendrimers once absorbed into the systemic circulation. Of these few studies, Gillies et al. have examined the pharmacokinetics of PEGylated, ‘bow-tie’ polyester dendrimers and shown that dendrimer clearance mechanisms are highly dependent on the molecular weight and flexibility of the complex,12 Kobayashi et al. have examined the effect of structural changes on the biodistribution of dendrimers designed to facilitate heavy metal or antibody complexation (and therefore application in bio-imaging)13-17. To this point, however, the intrinsic systemic pharmacokinetics of polylysine dendrimers have not been described in any detail.
Further, it is still a challenge to prepare dendrimers that circulate in the blood long enough to accumulate at target sites, but that can also be eliminated from the body at a reasonable rate to avoid long-term build up. In addition, the tissue localisation of dendrimers is still difficult to predict in advance and more studies are required to determine the effect of peripheral dendritic groups on these properties. An additional area that needs to be investigated is the release of drugs from dendrimers. Steric hindrance associated with the dense globular dendritic architecture makes the engineering of the enzymatically cleavable linkages difficult.
It is, accordingly, an object of the present invention to overcome or at least alleviate one or more of the difficulties and/or deficiencies related to the prior art.